Infections with gram-positive organisms are highly prevalent in hemodialysis patients and are a major cause of morbidity and mortality in this population. Antimicrobial therapy is widely used to treat these infections, and prolonged therapy with these agents is often necessary. Extensive use of antimicrobials in hemodialysis patients has resulted in a growing threat of resistance, especially among gram-positive bacteria such as Enterococcus spp and Staphylococcus aureus. Vancomycin-resistant enterococci and S. aureus isolates with reduced susceptibility to vancomycin are increasingly being reported in hemodialysis patients. Additionally, resistance of these organisms to newer agents, such as linezolid and daptomycin, has been documented. Appropriate utilization of antimicrobial therapy to treat these organisms requires an understanding of the pharmacokinetic and pharmacodynamic principles to optimize therapy and avoid adverse drug events. The pharmacokinetic and pharmacodynamic profile of antimicrobial agents can be significantly altered in patients with chronic kidney disease. This review will describe mechanisms of antimicrobial resistance among common gram-positive organisms. The pharmacokinetic and pharmacodynamic principles of cephalosporins, vancomycin, aminoglycosides, linezolid, and daptomycin and applications for use of these agents in the treatment of patients with bloodstream infections on hemodialysis are discussed.